Abstract
Ataxia-telangiectasia (AT) is a complex, autosomal recessive disorder characterized by cerebellar ataxia, believed to result from progressive neurodegeneration, and telangiectasia, dilation of blood vessels within the eyes and parts of the facial region. AT patients suffer from recurrent infections caused by both cellular and humoral immune deficiencies and as a population, are significantly predisposed to cancer, particularly lymphomas and leukemias. Early attempts at treating these malignancies with radiotherapy revealed another hallmark of AT, a profound hypersensitivity to the cytotoxic effects of ionizing radiation (IR) which is recapitulated at the cellular level in culture. Predisposition to cancer and radiosensitivity observed in AT has been linked to chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage. These earlier observations predicted that the gene defective in AT may encode a protein which plays a crucial role in sensing DNA damage and transducing signals that promote cell survival. Through the combined efforts of linkage analysis and positional cloning, a single gene was identified on chromosome 11q22-33 by Shiloh and colleagues and was found to be mutated in all four complementation groups previously characterized in cell lines derived from AT patients (,). The predicted ATM gene product shows considerable homology to an emerging family of high molecular weight, phosphatidylinositol -3 kinase (PI-3 K)-related proteins involved in eukaryotic cell cycle control, DNA repair, and DNA recombination (). This landmark discovery has triggered a resurgence of biochemical and genetic studies focusing on ATM function which has brought forth insights regarding ATM activity and its role in DNA damage signaling.
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Canman, C., Lim, DS. The role of ATM in DNA damage responses and cancer. Oncogene 17, 3301–3308 (1998). https://doi.org/10.1038/sj.onc.1202577
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DOI: https://doi.org/10.1038/sj.onc.1202577
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